Process for preparation of 3-amino-1, 3, 5(10)-estratriene derivatives



3,6@,Zfl Patented Oct. 23, 1962 3 Claims. (Cl. 269-3975) This invention relates to novel, therapeutically active amino steroids and derivatives thereof and to methods for their preparation. More specifically, our invention relates to aminoestratrienes and, in particular, to 3-amino- 1,3,5 ()-estratrienes which possess an oxygen function at C-l7, and to the derivatives thereof.

The novel aminoestratrienes of our invention are represented by the following formula; and include their salts with acids:

wherein X is a member of the group consisting of O, (H, 3OZ), (a-methyLfiOZ), and (a-ethinyLflOZ) wherein Z is a member of the group consisting of H and acyl; and R and R may be the same or different and are members of the group consisting of H, lower alkyl, benzyl or acyl.

By the term acyl is contemplated acid radicals of hydrocarbon carboxylic acids preferably having up to eight carbon atoms. Included in this group are aromatic acids exemplified by benzoic acid or alkyl substituted benzoic acids and, preferably, lower alkanoic acids such as formic, acetic, phenylacetic, propionic, t-butylacetic, Valerie, caproic and the like.

The term alkyl includes hydrocarbon radicals containing up to six carbon atoms and, preferably, up to four carbons including methyl, ethyl, n-propyl, isopropyl, nbutyl, sec.-buty-l and t-butyl.

The aminoestratrienes of the general formula possess estrogenic activity as well as anti-gonadotropic and antiandrogenic properties. They are thus useful as a pituitary gonadotrophin inhibitor in relieving menopausal symptoms as well as treating conditions such as arteriosclerosis. In addition, acyl compounds such as 3-(N-acetylamino)- 1,3,5 (10)-estratriene-l7B-ol 17-acetate possess analgesic properties. Our novel aminoestratrienes can be administered orally to the animal organism in conventional dosage forms such as pills, capsules, tables, syrups or elixirs; or by injection in liquid forms adaptable for steroid administration. The salts of the compounds of our invention advantageously are water soluble thus making them particularly valuable as drugs via both the oral and parenteral routes.

Of the novel compounds encompassed by the general formula, the preferred group are those wherein at least one of R and R are acetyl. The novel 3-aminoestratrienes while being therapeutically active are also useful as intermediates in preparing the preferred S-(N-acylamino) and 3 (N,N-diacylamino -estratrienes.

Our novel 3-aminoestratrienes may be prepared either through the rearrangement of an oxime of a 3-keto-A -l9- nor steroid such as l9-nortestosterone or through the reaction of a lO-quinol acetate such as lOi-acetoxy-lA- estradiene-3,17-dione with benzylamine. In the former process, 19-nortestosterone, for example, is converted to l9-nortestosterone oxime according to known procedures utilizing hydroxylamine hydrochloride. The 19- nortestosterone oxime intermediate is then converted to a 3-amino-aromatic A-ring steroid of our invention by reaction at elevated temperatures (usually at reflux) with a lower alkanoic acid anhydride such as acetic anhydride to give 3(N-acetylamino)-l,3,5(10)-estratriene- -01 17-acetate, a novel compound of our invention By subjecting the 3-(N-acetylamino)-estratriene thus obtained to strong acid hydrolysis such as that utilizing sulfuric acid followed by neutralization of the amine acid salt thereby formed, there is obtained 3-amino-1,3,5(10)- estratriene-17fi-ol.

When other lower alkanoic acid anhydrides such as propionic or butyric anhydrides are substituted for acetic anhydride in the aforementioned procedure, l9-nortestosterone oxime is converted to the corresponding 3-(N- acylamino)-estratriene, i.e. 3-(N-propionylamino)-1,3,5 (10)-estratriene-l7fi-ol 17-propionate and B-(N-butyrylamino)-1,3,5 lO)-estratriene-17,8-ol 17-butyrate, respectively.

According to our process, the 3-oxime of any S-keto- A -19-nor steroid may similarly be boiled with a lower alkanoic acid anhydride and there will be obtained the corresponding 3-(N-acylamino) 1,3,5(10)-tridehydro steroid. For example, l9-norethisterone (17x-6thiDYl-19- nor-4-androstene-17 8-01-3 -one) when reacted with hydroxylamine hydrochloride gives 19-nor-ethisterone oxime which upon reaction with acetic anhydride according to our process yields a novel compound of our invention, 3-(N-acetylamino) 17cc ethinyl-l,3,5(10)-estratriene- 17,6-01 17acetate. Similarly, 17a-ethyl-l9-nortestosterone is converted to -17u-ethyl-l9-nortestosterone oxime which is boiled with acetic anhydride to give the novel 3-(N- acetylamino)-17a-ethyl, 1,3,5 10) -estratriene-l 7,8-01 17- acetate. Strong acid hydrolysis of each of the aforementioned tertiary alcohols followed by neutralization with a weak base such as sodium carbonate yields the corresponding free amine, i.e. 3-amino-17a-ethinyl-1,3,5 (10) -estratriene-17;3-ol and 3-amino-17ot-ethyl-1,3,5 10) estratriene-17/3-ol.

Alternatively, according to our process indicated below wherein are prepared the novel 3-aminoestratrienes of this invention, an amino group is introduced at the 3- carbon of a steroidal 3-keto-quinol acetate such as 10%- acetoxy-1,4-estradiene3,17-dione (II) by condensation with a primary amine, preferably benzylami-ne. An intermediary Schiff base (III) is formed which rearranges With the loss of acetic acid yielding a second intermediary Schiif base (IV), which, upon acid hydrolysis followed by neutralization of the amine acid salt thereby formed,

In actual practice, the intermediary bases III and IV are not necessarily isolated. The quinol acetate 11 and an excess of primary amine are refluxed together for a period of from one to four hours (when benzylamine is used, preferably about 2 /2 hours). The intermediary Schifi base thus obtained need not be isolated but is hydrolyzed by heating the reaction mixture in the presence of an acid such as sulfuric acid. The amine salts thereby formed are conveniently neutralized by making the reaction mixture basic with sodium bicarbonate, for example, and extracting the novel amine product (I) with an organic solvent such as methylene chloride.

Although benzylamine is preferred in carrying out our inventive process, other primary amines may be used such as those of the general formula GENE:

RI wherein R and R may be alike or dissimilar and at least one of the substituents Rand R is phenyl, p-chlorophenyl, or other similar aromatic residues. When R and R are not alike the dissimilar substituent may be hydrogen or an alkyl residue such as methyl, ethyl and the like. Other amines which may be used in our process are those containing a carbonyl group on the carbon alpha to the amine group, for example, arninoacetone (NH CH COCH may be carried out in the presence of a solvent. Aside from the consideration of solubility, the solvating medium preferably boils in the range of C. to 200 C. Benzylamine is both the amine and solvent of choice in preparing the novel 3-amino steroids not only because of its high boiling point (187 0), its high basicity, and relatively unhindered nature, but also because of the activation by the phenyl group of the hydrogen atoms alpha to the nitrogen. Other solvents which may be used are xylene or durene.

The starting compound, 1OE-acetoxy-l,4-estradiene-3, 17-dione mentioned above was used for illustrative purposes. Other lQE-acetoxy steroidal quinols may be used as starting compounds such as IOE-acetoxy-1,4-estradiene- -ol-3-one, lOE-acetoxy-lh-methyl-l,4-estradiene-17fi- 01-3 one, 10$-acetoxy-l7 x-ethinyl-1,4-estradiene-17/3-ol- 3-one and the 17-esters thereof. These starting compounds are prepared from their corresponding S-hydroxy- 1,3,5(10)-estratrienes by oxidation with lead tetra-acetate as described by Gold and Schwenk in J. Am. Chem. Soc. 80, 5683 (1958). Thus, estrone (l,3,5(l0)-estratriene- 3-ol-l7-one) when oxidized with lead tetra-acetate in acetic acid yields lOZ-acetoxy-1,4-estradiene-3,17-dione (compound II). In like manner, estradiol (1,3,5(10)- estratriene-3,i17 fi-diol) 17a-methyl-l ,3 ,5 l0 -estratriene- 3,17fi-diol, and the like, when reacted with lead tetraacetate and acetic acid are converted to l'OE-acetoxy-lA- esteradiene-l7fi-ol-3-one and lOE-acetoxydh-methyh1,4- estradiene-l7[3-ol-3-one, respectively.

Although the lOE-acetoxy-1,4-diene-3-one steroids described above are the starting compounds of choice, the corresponding lOE-hydroxy steroid or other 10-lower alkanoic acid esters thereof may also be used as intermediates for our novel process. The 10i-hydroxy steroids, for example, IOE-hydroxy-l,4-estradiene-3,l7-dione, are obtained from the corresponding IOE-acetates by means of an alkali metal alcoholate such as sodium methoxide in methanol as described by Gold and Schwenk supra. Other lower alkanoyl ester intermediates such as lOE-propiOnyloxy-1,4-estradiene-3,17-dione are prepared by the oxidation of a starting material such as 3-hydroxy-l,3,5(l0)-estratriene-17-one in the same manner as are the l0g-acetoxy compounds by replacing lead tetra-acetate by the corresponding lead salt of propionic acid or by the use of propionic acid together with lead oxide. Other alkanoic acids such as caproic or valeric can be used in the place of propionic acid.

Although the l7a-methyl-17B-hydroxy and 17a-6illiI1Yll7B-hydroxyestratrienes of our invention may be prepared from the corresponding 17 substituted-l0; acetoxy-l,4- estradiene intermediates or from the oximes of Not-methyl-l9-nortestosterone and 17oc-ethinyl-19-nortestosterone according to the heretofore described processes, it is preferred to introduce these groups following the introduction of the 3-amino group into the molecule. Thus, the 17tx-methyl-l7B-hydroxy-3-aminoestratrienes of the general formula are prepared from 3-arnino-l,3,5,(10)-estratriene-l7-one (or an N-substituted derivative thereof) in conventional manner with, for example, an alkyl lithium reagent such as methyl lithium in ether at low temperatures or with a Grignard reagent such as methyl magnesium iodide in ether.

The l'l-keto-S-aminoestratrienes are also convertible to the l7ot-ethinyl-17p-hydroxy derivatives. In particular, the l7-keto group is transformable into the l7ot-ethinyl-17fihydroxy function by reaction with sodium acetylide in liquid ammonia.

Our 17-hydroxy-arninoestratrienes are also convertible to the 17u-ethinyl-17 8-hydroxy and l'ia-methyl-flp-hyroxy analogs by first oxidizing the l7B-hydroxy group to l7-keto in a conventional manner and then proceeding as above.

The N-substituted derivatives of our invention are prepared from the corresponding 3-aminoestratrienes by using conventional reactions. Thus, treatment of B-amino- 5 1,3,5 (10)-estratriene-17fi-ol with methyl iodide, in an insert solvent, for example, yields either 3-(N-methylamino) 1,3,5 (l)-estratriene-17,8-ol or 3-(N,N-dimethylamino)- 1,3,5 lO)-estratriene-17fi-ol depending on the amount of methyl iodide used and the length of the reaction time.

In a similar fashion, the N-benzyl derivatives of our invention, such as 3-(N-benzylamino)-1,3,5(10)-estratriene-175-ol is obtained by reacting the free amino com pound, e.g. 3-amino- 1,3,5 10)-estratriene-17fl-o1, with a benzylhalogenide in conventional manner, or by reduction of the Schiif base IV as obtained by heating 10-acetoxy 1,4 estratriene 17,8-01-3-one with benzylamine as heretofore described, omitting the subsequent treatment with acid.

The N-acyl derivatives are conveniently prepared from the corresponding 3-aminoestratrienes by reaction with an acid anhydride or chloride in the presence of pyridine. For example, 3-amino-l,3,5(l0)-estratriene-17-one when reacted with acetic anhydride and pyridine yields 3-(N- acetylamino)-l,3,5(l0)-estratriene-l7-one. Any free hydroxyl groups which may be present are also esterified under these reaction conditions. Thus, 3-amino-l,3,5(10) estratriene-17,8-ol when reacted with acetic anhydride and pyridine is converted to 3 (N actylamino) 1,3,5 (10)- estratriene-17/3-ol l7-acetate.

Acetic anhydride may be replaced by anhydrides of other acids in the above procedures and the corresponding N-acyl derivatives are obtained. Thus, pyridine in conjunction with an acid anhydride such as butyric anhydride or benzoyl chloride when reacted with a 3-aminoestratriene of formula I will form the corresponding 3-(N- acylamino)-estratriene, i.e. a 3-(N-butyrylamino) and 3- (N-benzoylamino)-estratriene, respectively.

By changing the amounts of reactants in the above described procedures and modifying reaction conditions such as temperature and length of reaction time, one can obtain either a monoor di-N-acyl or N-alkyl derivative, whichever is desired.

Convenient methods of obtaining an estratriene of our invention possessing a 3-N-acyl and a 17-hydroxy group are by treating the free 3-amine with an acid, formic acid, thus forming a B-(N-formylamino)-17-hydroxyestratriene for example, or by shaking an aqueous suspension of the 3-amino derivative with an acid anhydride such as acetic anhydride to obtain a 3-(N-acetylamino)-17-hydroxyestratriene. For example, 3-amino-17a-ethinyl-L3, 5(l0)-estratriene-175-ol reacted with aqueous acetic anhydride yields 3-(N-acetylamino)-l7a-ethinyl 1,3,5()- estratriene-17B-ol.

Novel 3-aminoestratrienes of our invention wherein the hydrogens of the amino group are replaced by dissimilar groups neither of which is hydrogen, such as in 3-(N-benzyl-N-acetylamino)-1,3,5(10) estratriene 175-01 17 acetate are obtained by adding the appropriate reagent to a monosubstituted derivative. For example, by reacting an N-monosubstituted aminoestratriene such as 3-(N-benzylamino)-l,3,5(10)-estratriene-17fi-ol with acetic anhydride in pyridine there is obtained 3-(N-benzyl-N-acetylamino)- estratriene-l7B-ol l7-acetate.

Acid addition salts of the 3-aminoest-ratrienes of the general formula such as the phosphoric acid salt, the sulfuric acid salt or the hydrochloric acid salt of 3-amino-l, 3,5(10) estratriene 17B 01, are conveniently prepared from the corresponding free amine according to known techniques. For example, an equimolar quantity of anhydrous hydrogen chloride in methanol added to a methanolic solution of 3 amino-1,3,5(10) estratriene 1713-01 yields the novel 3-amino-1,3,5(10)-estratriene-17[3-ol hydrochloric acid salt.

The following examples are illustrative of methods by which the novel compounds of our invention may be made and are not to be construed as limiting the scope of the invention, the scope of our invention being defined by the appended claims.

This application is a division of copending applicatio Serial No. 24,915, filed April 27, 1960.

EXAMPLE 1 3-Amin0-1,3,5 (10 -Estratriene-17-One A solution of 0.5 g. of '10i-acetoxy-1,4-estradiene-3,17- dione in 5 ml. of benzylamine is refluxed for 2 /2 hours. Most of the benzylamine is removed from the reaction mixture by warming in a stream of nitrogen and the residue is then refluxed with 50 ml. of 2 N sulfuric acid for two hours. The reaction mixture is then cooled, extracted with ether, made alkaline with solid sodium carbonate and then extracted with methylene chloride. The latter organic extracts are combined, dried over sodium sulfate and evaporated to a residue. Ten m1. of cyclohexane is added to the residue and left at room temperature for a short time. The crystalline precipitate separates and is filtered and sublimed at 140 C. (0.01 mm.). The resulting white powder is recrystallized several times from benzene-cyclohexane to yield 3-amino-1,3,5(10)- estratriene-17-one, M.P. l92-192.6 C.

A 2538 my (9,100), 292 mu (1,900) [a]' +60 (chloromax.

form

Analysis.-Calcd. for C H ON N, 5.20. N, 5.62.

Found:

To a solution of mg. of 3-amino-l,3,5(10)-estratriene-l7-one (the compound of Example 1) in 1 ml. of pyridine, there is added 0.2 ml. of acetic anhydride and the mixture is allowed to stand at room temperature for one hour. Water (10 drops) is added and after one hour 10 ml. of 2 N sulfuric acid is added. A precipitate is formed which is filtered, washed with water and recrystallized from aqueous methanol to give a product which is sublimed at 195 C. (0.02 mm.) and is recrystallized twice from aqueous methanol to give 3-(N-acetylamino)- l,3,5(l0)-estratriene-l7-one, M.P. 255256 C.

AMEOH 247 mu (15,500), 289 mu (1, [11]? 161 (dimethmax.

ylformamide) Analysis.-Calcd. for C H O N: C, 77.13; H, 8.09; N, 4.50. Found: C, 77.43, 77.61; H, 8.12, 8.24; N, 4.59.

In a similar manner, by substituting other lower alkanoic acid anhydrides such as caproic anhydride and propionic anhydride for acetic anhydride in the above procedure the corresponding 3 (N acylamino) estratrienes are obtained, i.e. 3-(N-caproylamino)-1,3,5(10)- estratriene-l7-one and 3-(N-propion-ylarnino) -1,3,5 l0)- estratriene-l7-one, respectively.

EXAMPLE 3 3-Amin0-1,3,5 (10) -Estratriene-17,B-Ol A. THE SULFURIC ACID SALT OF 3-AMINO-1,3,5(1'0) ESTRATRIENE-IYfiOL A solution of 0.30 g. of l0i-acetoxy-l7fl-hydroxy-1,4- estradiene-3-one in 3 ml. of benzylamine is refluxed for two hours. From the reaction mixture the benzylamine is evaporated in a stream of nitrogen. To the resultant residue is added 5 ml. of 2 N sulfuric acid and 25 ml. of water and the mixture distilled to half the original volume. The residue from this distillation is refluxed for 1 /2 hours, then cooled. A precipitate separates which is isolated by filtration, washed with water and dry ether, dried and recrystallized three times from methanol to give the sulfuric acid salt of 3-amino-1,3,5(10)-estratriene-lZB-ol which decomposes at 320 C.

Analysis.-Calcd. for C H ON. /2H SO N, 4.37; S, 4.99. Found: N, 4.32; S, 5.10.

B. 3-AMINO1,3,5 (1O -ES'IRATRIENE-17BOL A1452 237 mu (7,900), 292 mu (1,500) [a], +71 (chloroform) EXAMPLE 4 Hydrochloric Acid Salt of 3-Amin0-1,3,5(10)- Estratriene-I 713-01 To 3-amino-1,3,5(10)-estratriene-175-ol (the compound of Example 2) in methanol is added an equimolar quantity of anhydrous hydrogen chloride in methanol. Water is added and a precipitate results which is crystallized from methanol-water three times and finally with anhydrous methanol to give the hydrochloric acid salt of 3-amino-l,3,5(10)-estratriene-17/3-ol, M.P. 274 C.

Analysis.-Calcd. for C H ON.HCl: C, 70.22; H, 8.51; N, 4.55; Cl, 11.53. Found: C, 70.32, H, 8.58; N, 4.00; Cl, 11.61.

EXAMPLE 5 3-(NAcetylamin0'-1,3,5 -Estratriene1 75-01 1 7-Acetate A. IQ-NORTESTOSTERONE OXIM'E To a solution of 2.42 g. of 19-nortestosterone in 30 ml. of methanol is added a solution of 1.86 g. of hydroxylamine hydrochloride and 5 g. of sodium acetate hydrate in 10 ml. of water. The mixture is refluxed on the steam bath for three hours and the methanol evaporated until the reaction mixture is a saturated solution. The solution is seeded and slowly cooled. The resulting precipitate is filtered and dried in vacuo to give l9-nortestosterone oxirne which is used without further purification in the following procedure.

B. (N-ACETYLAMINO)-1,3,5 (10)-ESTRATRIENE-17fi-OL 17-ACETATE The crude oxime as prepared in Example 5A is refluxed for three hours with 25 ml. of acetic anhydride and then is poured into 250 ml. of cold water. The mixture is allowed to stand for one hour with occasional stirring and then is extracted with chloroform. The organic extracts arecombined, washed with water and potassium bicarbonate solution, dried over sodium sulfate and evaporated to a residue which is chromatographed on 80 g. of neutral alumina. The material is introduced onto the column in a benzene solution and eluted with 500 ml. each of benzene, 10% chloroform-benzene and 30% chloroformbenzene. The eluate is collected in 250 ml. fractions which are distilled to dryness in vacuo. The crystalline fractions are combined, dissolved in 30 ml. of hot benzene and 30 ml. of cyclohexane added. The solution is heated to boiling, then cooled. A precipitate results which is filtered, dried and recrystallized from anhydrous methanol to give 3 (N acetylamino)-1,3,5(l0)-estratriene-17fi-ol-17-acetate, MP. 207.5209.8 C.

A1 32 249 mu (15,000) inflection aft-(273 m [a]%+ (chloroform) Analysis-Called. for C H O N: C, 74.33; H, 8.22; N, 3.94. Found: C, 74.27; H, 8.29;. N, 3.92.

Alternatively, the compound of this example is prepared by the following procedure.

C. 3-(N-ACETYLAMINO)-1,3,5 (10)-ESTRATRIENE-17B- OL 17-ACETA'1E To 10 mg. of 3-amino-1,3,5(10)-estratriene-17B-ol (the compound of Example 3) is added 0.5 n11. of pyridine and 0.1 ml. of acetic anhydride. The reaction mixture is allowed to stand'at room temperature for two hours. Water is added and after one hour 10 ml. of 2 N sulfuric acid is added. A precipitate forms which is filtered, washed with water, recrystallized from aqueous methanol, then sublimed at 195 C. (0.02mm.) to yield a solid product which is recrystallized from methanol and dried at 100 C. in

' Example 3) is reacted 175-01 17-acetate, MP. 210214 C. (There is nodepression in the melting point taken of a mixture of the product produced by procedure C with that of procedures A and B.)

EXAMPLE 6 3 (N -Caproy lamina) -1 ,3 ,5 (10)-Estratriene-1 -01- 7-Capr0ate 3amin0-1,3,5(10)-estratriene-l7fl-ol (the compound of with caproic acid anhydride and pyridine in a manner similar to that described in Example 5C. The resultant product is isolated in the described manner and crystallized from aqueous methanol to give 3- (N-caproylamino) -1,3 ,5 10) -estratriene-17 [3-01 17-caproate.

EXAMPLE 7 3-Amin0-1 7a-Ethin) l-l ,3 ,5 1'0) -Eslratriene-1 75-0! 300 mg. of potassium is dissolved with stirring in ml. of liquid ammonia in a dry atmosphere. A stream of acetylene is passed into the stirred cold solution until absorption is complete and the color has changed completely. While continuinga slow stream of acetylene, a solution of 500 mg. of 3-amino-1,3,5(10)-estratriene-l7- one (the compound of Example 1) in 10 ml. of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture is stirred for two hours after which, 1 ml. of water is carefully added dropwise to decompose any excess reagent. The solution is then allowed to evaporate by warming to room temperature followed by evaporation in vacuo. The resulting residue is crystallized from ethanol to give 3-amino-17-or-ethinyl-1,3,5 10)-estratriene-l7 [3-01.

EXAMPLE 8 3-Amino-1 7 oc-M ethyl-1 ,3,5 (10 -Estratriene-1 7fl-Ol To a solution of 500 mg. of 3-amino-1,3,5(l0)-estratriene-17-one (the compound of Example 1) in 5 ml. of dry anisol under an atmosphere of nitrogen, there is added with stirring a solution of 1.1 g. of methyl magnesium iodide in 5 ml. of ether. The addition is maintained dropwise at such a rate that the heat generated maintains the reaction mixture at reflux temperature. After the addition is complete, the mixture is refluxed with stirring for two hours. The mixture is then cooled and a saturated solution of aqueous ammonium chloride added. The aqueous layer is separated and the organic solution is washed with water to neutrality, dried over magnesium sulfate, filtered and evaporated in vacuo to a residue which is crystallized from acetone-hexane to give 3-amino-17w methyl-1,3,5( l0 -estratriene-1'7 [3-01.

EXAMPLE 9 fi-(N-Dimethylamino) -1,3,5 (10) -Estratriene-1 7B-Ol EXAMPLE 10 3-(N-Bcnzylamino -1,3,5 (10) -Estratrz'ene-1 73-01 To a solution of 3-amino-1,3,5(10)-Estratriene-17fl-ol (the compound of Example 3) in 5 ml. of dry tetrahydrofuran is added 4.5 ml. of benzyl bromide. The mixture is stirred and refluxed for one hour and evaporated in vacuo to a residue which is triturated with aqueous sodium bicarbonate solution. The resultant solid is collected by filtration and crystallized from aqueous acetone to give vacuo to give 3-(N-acetylamino) -1,3 ,5 10 -estratriene- 75 3-(N-benzylamino)-1,3,5(10)-estratriene-l7B-o1.

9 EXAMPLE 1 1 3- (N -M ethylamino) ,3,5 (10) -Estratriene-J 7 fl-ol EXAMPLE 12 S-(N-Acetylamino)-]7a-Methyl-1,3,5(10) -Estrazriene- 1 73-01 17-Acetate In a manner similar to that described in Example 50, 3 amino-l7a-methyl-1,3,5(10)-estratriene-17fl-o1 (the compound of Example 8) is reacted with acetic anhydride and pyridine and the resultant product isolated and purified to give 3-(N-acetyl-amino)-17u-methyl-1,3,5(10)- estratriene-l7fl-ol 17-acetate.

EXAMPLE l3 3- (N-Benzy l-N-A cely lam ino) ,3,5 (1 -Estratriene- I 7 3-0l 1 7-A cezate In a manner similar to that described in Example C, 3-(N-benzylamino)-1,3,5(10)-estratriene-17fl-ol (the compound of Example is reacted with acetic anhydride and pyridine to give 3-(N-benzyl-N-acetylamino)-1, 3,5 l 0) -estratriene-17,B-ol 17-acetate.

EXAMPLE 14 3 (N -M elhyl-N -A cetylamino) -1,3,5(10) -Estrazriene-1 7 ,6- ol 1 7-A estate In a manner similar to that described in Example 5C, 3-(N-methylamino)-1,3,5(10)-estratriene-17B-ol (the compound of Example 11) is reacted with acetic anhydride and pyridine to give 3-(N-methyl-N-acetylamino)- 1,3,5 10)-estratriene-17fi-ol 17-acetate.

EXAMPLE l5 3- (N -A cety lamina 7a-Ethinyl-1 ,3,5 (1 0 -Eszratriene- 17fi-0l 1 7-Acetate A. 17a-ETHINYL-19-NORTESTOS'IERONE OXIME In the manner described in Example 5A, l7a-ethinyll9-nortestosterone is reacted with hydroxylamine hydrochloride and sodium acetate. The resultant product is isolated in the described manner .to give 17a-ethiny1-19- nortestosterone oxime.

B. s- (N-ACE'IYLAMINO -17a-ETHINYL-1,3,5 10 Es'rRA- TRIENE-l'Yfl-OL 17 -ACETATE In the manner described in Example 5B, 17a-ethinyl- 19-nortestosterone oxime is reacted with acetic anhydride. The resultant product is isolated and purified as described to give 3-(N-acetylamino)-l7a-ethinyl-l,3,5(10)-estratriene-17fi-ol l7-acetate.

Alternatively, the compound of this example is prepared as follows:

To 10 mg. of 3-amino-17u-ethinyl-l,3,5(10)-estratriene- 176-01 (the compound of Example 7) is added 0.5 ml. of pyridine and 0.1 ml. of acetic anhydride. The reaction mixture is left overnight at room temperature. Water is added and after one hour 10 ml. of 2 N sulfuric acid is added. A precipitate forms which is filtered, washed with water and recrystallized from aqueous methanol to give 3 N acetylamino-l7a-ethinyl-l,3,5(10)-estratriene- 175-01 17-acetate.

EXAMPLE 16 3 (N -Benz0ylamin0 7 oc-M ethyl-1 ,3,5 (10) -Eszratriene- 10 mg. of 3-amino-17m-methyl-l,3,5(10)-estratriene- 175-01 (the compound of Example 8) is reacted with 0.1

ml. of benzoyl chloride and 0.5 ml. of pyridine in a manner similar to that described in Example 5C. The resultant product is isolated in the described manner to give 3- benzoylamino) -l 7a-methyl-1,3,5 10) -estratriene-17;8-ol.

EXAMPLE l7 3- (N -M ethyl-N -Benzylamin0) ,3 ,5 (10) -Estratriene- J 7-Orze A. 3- (N -METHYLAMIN O -1,8,5 (10 -ESTRATRIENE-1 T-ONE In a manner similar to that described in Example 11, 3-amino-l,3,5(10)-estratriene-l7-one (the compound of Example 1) is reacted with methyl iodide in tetrahydrofuran to give 3-(N-methylamino)-1,3,5(l0)-estratriene- 17-one.

B. s- (N-METHYL-N-BENZYLAMINO) 4,3,5 10 -ESTRA- TRIENE-l'Y-ONE In a manner similar to that described in Example 10, 3- (N-methylamino) 1,3,5 10)-estratriene-17-one in tetrahydrofuran is reacted with benzyl iodide. The resultant product is isolated and purified as described to give 3-(N- methyl-N-benzylamino)-1,3,5 10) -estratriene-l7-one.

EXAMPLE 18 3- (N-Diacetiylamino) 1,3,5 (10) -Eszratriene-J7-One To a solution of 800 mg. of 3-amino-l,3,5(10)-estratriene-17-one (the compound of Example 1) in 2 ml. of pyridine, there is added 1 ml. of acetyl chloride and the mixture is allowed to stand overnight at room temperature. Water is added and after one hour, 10 ml. of 2 N sulfuric acid is added. A precipitate forms which is filtered, washed with water and recrystallized from aqueous methanol to give 3-(N-diacetylamino)-1,3,5-(10)-estratriene-l7-one.

We claim:

1. In the process of preparing compounds of the group consisting of estratriene derivatives of the following formula and the pharmaceutically acceptable acid addition salts thereof;

wherein X is as above defined, and isolating the 3-(N- lower alkanoylamino)-estratriene thereby formed, said HON= 11 3-(N-l0wer alkanoylamino)-estratriene having the following formula:

12 wherein Y is a member of the group consisting of O, (HfiOR'), (a-rnethyLfiOR') and (ot-ethinyLfiOR) and R is lower alkanoyl.

2. The process of claim 1 wherein the lower alkanoic acid anhydride is acetic anhydride.

3. The process which comprises heating at reflux temperature a mixture of 19-n0rtest0ster0ne oxime and acetic anhydride, and isolating the 3-(N-acetylamino)-1,3,5 (10)-estratriene-17fi-0l-17-acetate thereby formed.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,060,205 October 23, 1962 Erwin Schwenk et ale It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 11 lines 4 to 1O the structural formula should appear as shown below instead of as in the patent:

RN H

Signed and sealed this 19th day of March 1963.

(SEAL) Attest:

' DAVID L,. LADD Attesting Officer 

1. IN THE PROCESS OF PREPARING COMPOUNDS OF THE GROUP CONSISTING OF ESTRATRIENE DERIVATIVES OF THE FOLLOWING FORMULA AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF; 